Indications

Acetaminophen (APAP) is a non-opioid analgesic and antipyretic agent used to treat pain and fever. Clinicians can use it for their patients as a single agent for mild to moderate pain and in combination with an opioid analgesic for severe pain.

Mechanism of Action

Acetaminophen, also called N-acetyl para-aminophenol or paracetamol, is one of the most widely used over-the-counter analgesic and antipyretic agents.[1] Although its exact mechanism of action remains unclear, it is historically categorized along with NSAIDs because it inhibits the cyclooxygenase (COX) pathways.[2][3] Like NSAIDs, acetaminophen has analgesic and antipyretic properties. However, studies have shown that acetaminophen lacks peripheral anti-inflammatory properties. It may be that acetaminophen inhibits the COX pathway in the central nervous system but not peripheral tissues. Additionally, acetaminophen does not appear to bind to the active site of either the COX-1 or COX-2 enzyme, instead of reducing the activity of COX by a different mechanism. It also has been theorized that acetaminophen inhibits a splice variant of COX-1, also called COX-3, but this has not been confirmed to occur in humans.[4] Regardless, the reduction of the COX pathway activity by acetaminophen is thought to inhibit the synthesis of prostaglandins in the central nervous system, leading to its analgesic and antipyretic effects. The analgesic properties may be due to a stimulating effect on the descending serotonergic pathways in the central nervous system (CNS). Other studies have suggested that acetaminophen or one of its metabolites also can activate the cannabinoid system, contributing to its analgesic action.

Administration

Acetaminophen can be administered orally, rectally, or intravenously (IV).[5]

Oral: Acetaminophen is available as a tablet, capsule, syrup, oral solution, or suspension.

Rectal: Acetaminophen is available as a rectal suppository for both adult and pediatric patient populations.

Intravenous: Acetaminophen also comes as an IV infusion for administration.

Adverse Effects

Adverse effects of acetaminophen administered orally or rectally may include the following:

Rare but serious adverse effects include hypersensitivity and anaphylactic reactions as well as serious and even fatal skin reactions. These include toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and Stevens-Johnson syndrome.

US Boxed Warnings

Hepatotoxicity:

Acetaminophen use has been linked to liver failure and sometimes has led to liver transplant or death. The hepatotoxicity seen with acetaminophen use typically correlates with high doses of acetaminophen that exceed the recommended maximum dose.[6] This effect may involve the intake of more than one drug product that contains acetaminophen as an ingredient. Liver damage also has been seen in patients with chronic dosing of acetaminophen.

Injection:

There is also a US boxed warning to avoid dosing errors, particularly when administering acetaminophen to pediatric patients, as well as making sure that the maximum total daily dose of acetaminophen does not exceed the recommended maximum when taking into account all medications that contain acetaminophen.

Although these effects, warnings, and associations have been documented, acetaminophen remains a safe and effective medication when used correctly. The current manufacturer dose recommendation is limited to between 3 and 3.25 grams in 24 hours, depending on the formulation. However, toxicity is rare at less than 150 mg/kg for an adult or 200 mg/kg for a child.

Contraindications

Contraindications to the use of acetaminophen include hypersensitivity to acetaminophen, severe hepatic impairment, or severe active hepatic disease. However, it is generally debated among experts if hepatic impairment is truly a limiting factor, as it would likely be associated with decreased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI).

Monitoring

Patients treated with acetaminophen should be monitored for desired clinical effects, such as pain or fever relief. Serum concentrations are unnecessary when appropriately dosed. In overdose settings, laboratory evaluation is necessary. In acute overdoses, in which ingestion occurs over less than eight hours, a serum APAP concentration should be assessed and plotted on the Rumack-Matthew nomogram, with the time course starting at the onset of ingestion, to determine toxicity and need for treatment. Nonacute ingestions require an assessment of acetaminophen concentration and transaminases, and treatment should occur.

Additionally, caution is necessary for patients with renal or hepatic impairment or patients with alcoholic liver disease, glucose six phosphate dehydrogenase deficiency, or severe hypovolemia. However, there is evidence that acetaminophen may be safe to use in the setting of alcoholic liver disease.[7]

Acetaminophen can cross the placental barrier, but there is no evidence of increased teratogenic effects due to the use of normal doses of acetaminophen during pregnancy.[8] Acetaminophen also is excreted into breast milk, but adverse reactions in nursing infants have not been widely observed.

Toxicity

Acetaminophen is responsible for an estimated 500 deaths and 50000 emergency department visits in the United States each year.[9] It is the most common drug-related cause of acute liver failure. The mechanism of hepatic injury is due to the drug metabolism properties of acetaminophen.[10] Following therapeutic levels of oral acetaminophen, 60% to 90% of the drug gets metabolized in the liver to glucuronic acid- and sulfate-conjugate metabolites. A smaller fraction (approximately 5% to 15%) undergoes metabolism by the cytochrome P450 system (CYP450). Metabolism primarily via CYP2E1results in the formation of the toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). Normally, NAPQI is neutralized by glutathione to nontoxic metabolites. However, with excessive doses of acetaminophen, the normal phase II drug metabolism pathways become saturated, and the CYP450 pathway metabolizes a higher portion of the acetaminophen taken, resulting in high levels of NAPQI formation, and the limited glutathione stores can become depleted. Without glutathione, NAPQI levels build up and NAPQI, as a reactive intermediate, can react with cellular macromolecules, proteins, lipids, and nucleic acids. This phenomenon can lead to centrilobular (Zone 3) hepatic injury and hepatocellular death.

The only approved antidote for acetaminophen overdose and toxicity is N-acetylcysteine (NAC).[11] NAC is a precursor to glutathione synthesis and helps to restore the intracellular stores of glutathione to neutralize the NAPQI compound. N-acetyl cysteine can be administered orally or by IV. IV N-acetyl cysteine is typically preferred because vomiting is common with acetaminophen overdose. It is effective if administered within the first few hours (up to 8 to 10 hours) of a toxic ingestion of acetaminophen. N-acetyl cysteine administration is as a 20-hour IV protocol or 72-hour oral protocol, and the AST/ALT of the patient requires monitoring during treatment.[12] One important thing to keep in mind is that most patients do not have symptoms in the first few hours of ingestion of toxic levels of acetaminophen and may only have abdominal pain and nausea as symptoms for the initial 12 to 24 hours. Between 24 and 72 hours, these symptoms may dissipate, although AST/ALT levels may be abnormal. Patients who present more than 24 hours following ingestion of toxic levels of acetaminophen may have symptoms such as nausea, vomiting, jaundice, abdominal pain, and hypotension. These patients may require airway management, intravenous fluids, vasopressors, hemodialysis, or management of cerebral edema or other symptoms as they arise.

Enhancing Healthcare Team Outcomes

The most crucial aspect of acetaminophen toxicity is prevention. Physicians, nurses, and pharmacists all share in this responsibility. Pharmacists and nurses need to emphasize the maximum dose permitted daily. Patients also need to understand how to look for acetaminophen in various medications they take and how to calculate the dose they receive when they combine products. Pharmacists need to perform medication reconciliation to look for drug interactions, as well as verify that there are not too many acetaminophen-containing drugs in the regimen. If there are concerns, they should be reported to the nurse and physician.

With the recent changes in maximum daily dosing for acetaminophen, all providers (physicians, nurses, and pharmacists) need to be aware of the new guidelines and remain current should any new guidance come out.

If toxicity occurs or there is suspicion of toxicity, management should be with an interprofessional team of physicians, nurses, and pharmacists. Specific protocols have been designed to direct a multi-disciplinary team of healthcare providers when patients present to emergency rooms with acute acetaminophen toxicity. One such protocol was designed by emergency physicians, nurses, toxicologists, pharmacists, and psychiatrists.[13] Dentists can also become involved if the overdose is secondary to dental procedures.[14] Importantly, upon discharge, patients should be provided with clear instructions on APAP medication management, as outlined above. While acetaminophen has been available for many years and is generally safe, a coordinated interprofessional team effort is necessary to avoid avoidable toxicity. [Level V]

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A mother brings her son who has asthma to the pulmonary clinic. She would like to know if she can give her child acetaminophen. She has heard reports that it may worsen asthma. What is the current consensus on acetaminophen and asthma?

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Smilkstein MJ,Knapp GL,Kulig KW,Rumack BH, Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) The New England journal of medicine. 1988 Dec 15 [PubMed]

Chandrasekharan NV,Dai H,Roos KL,Evanson NK,Tomsik J,Elton TS,Simmons DL, COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proceedings of the National Academy of Sciences of the United States of America. 2002 Oct 15 [PubMed]

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